The Hosomi-sakurai Reactions Of Isatins And Aldehydes Catalyzed By M(OTf)_n And Pybox

Hosomi-Sakurai reaction is one of the important reactions for synthesis of homoallylic alcohols and is also vital route for the carbon-carbon bond formation. Synthetic interests in homoallylic alcohols and analogues have increased very much over the past decade due to the notable biological activity and occurrence of this key structure in natural products and pharmaceutical lead compounds. Chiral C2-symmetric chiral bis(oxazoline) ligands(Box) are readily available from natural amino acid and their metal complexes have successfully applied in a variety of reactions, such as allylation of aldehydes or imines with allylstannane. Therefore, it is meaningful for further research on chiral oxazoline metal complexes in the Hosomi-Sakurai. In this paper, Hosomi-Sakurai reaction between aldehydes and allyltrimethylsilane was studied, and the reaction was catalyzed by chiral Lewis acid which are formed in situ from M(OTf)n and 2,6-bis[(S)-4-substitutedoxazolin-2-yl] pyridine(Pybox). In consideration of 3-substituted-3-hydroxyindolin-2-ones have the characteristic quaternary carbon structure and are the important structure in natural products and biologically active compounds as well, the research on the Hosomi-Sakurai reaction of N-substituted isatin were carried out, a series of 3-allyl-3-hydroxyindolin-2-ones were successfully synthesized. The thesis includes the following three parts:In the first part, the application of chiral bis(oxazoline) ligands in asymmetric synthesis are reviewed. Such as Diels-Alder reaction, cyclopropanation, Friedel-Crafts Alkylation reaction, Michael addition reaction, and so on.In the second parts, natural chiral amino acid acted as raw material, four kinds of chiral pyridine-2,6-bis(oxazoline) ligands were synthesized by reduction of carboxylic acid, acylation of amide, halogenation of hydroxyl groups, and acid or alkali catalyzed exo-tet cyclization reaction. Then, the Hosomi-Sakurai reaction between aldehydes and allyltrimethyl was catalyzed by chiral Lewis acid, which are in situ formed by coordination of metal salt M(OTf)n and Pybox ligands. The allylation of benzaldehyde with allyltrimethylsilane was selected as the model reaction; in which the metal salt, Pybox ligand types and dosage, solvent and dosage of reagents were optimized successively. The results show that the Ce(OTf)3/Pybox can efficiently catalyze the Hosomi-Sakurai reaction between benzaldehyde and allyltrimethylsilane with excellent enantioselectivity(up to >99% ee). It is worth mentioning that different solvents(CH2Cl2 or CHCl3) and ligand(or Pybox-1 or Pybox-3) combination can make the Hosomi-Sakurai reactions present consistent or complementary results and lead to aldehydes with different structure showing good to excellent enantioselectivity. Except 3-methylbenzaldehyde as substrate shows moderate enantioselectivity(78% ee), other aldehydes are demonstrated to have good to excellent catalytic selectivity(> 82% ee), especially benzaldehyde and thiophene-2-carbaldehyde obtained > 99% ee and 96% ee, respectively.In the third part, the Hosomi-Sakurai reaction of N-substitued isatin at the function of Lewis acid were explored. Lewis acid, dosage and solvent were screened to obtain the optimized reaction conditions. At last, the allylation of N-substitued isatin was accomplished with the Bi(OTf)3(20 mol%) as catalyst in CH2Cl2. A series of 3-allyl-3-hydroxyindolin-2-one compounds were obtained with the yields of 72-96%. In addition, it’s the reaction mechanism of Bi(OTf)3 catalyzed allylation of N-substitued isatin was studied at the same time.